Cisplafin (cis-diamminedichloroplatinum, CDDP) is an antineoplastic drug that has been used in cancer chemotherapy for a number of years. It is typically administered intravenously as an aqueous solution, either as a bolus injection or via infusion over a number of hours. It has been marketed both as a lyophilized powder for reconstitution into an aqueous solution, or as a ready-to-use aqueous solution. Intravenous delivery typically requires an aqueous solution, or, in some cases, a liquid emulsion or liposome system, wherein solid particulates which may occlude vessels and capillaries are absent. The concentration of CDDP in such intravenously injectable solutions is limited by its solubility in water, on the order of 1 mg/ml.
Cisplatin has also been administered in various forms for locoregional delivery, such as administration to the liver via infusion into the hepatic artery. In these cases, the drug can be administered in solution or emulsion forms above (for example, see Campbell et al. (1983) J. Clin. Oncol. 1:755-762). It can also be administered along with materials intended to bring about embolization in the target organ, thus blocking blood flow through that organ, inhibiting clearance of the CDDP away from the target organ. The cisplatin in these cases is typically in solution in water, but also may be combined with other nonaqueous materials such as iodized oil (Lipiodol; for example, see Araki et al. (1989) Gastrointest. Radiol. 14:46-48 or Feun et al. (1994) Am. J. Clin. Oncol. 17:405-410) or polyvinyl alcohol particles (Mavligit et al. (1993) Cancer 72:375-380). Unfortunately, this procedure is often associated with significant toxicity and morbidity to the patient, due to the blockage of blood flow to normal parts of the liver.
Another approach to the delivery of cisplatin to solid tumors has involved direct intralesional injection. Simple aqueous solutions of cisplatin have been reported for this use, as have simple oil/water emulsions and aqueous collagen gels. The dose of cisplatin achievable with these systems is, as above, limited by the solubility of cisplatin in water (approximately 1.2 mg/ml) and the volume of solution that can be successfully administered to the target tissue. Higher doses can produce an enhanced therapeutic gain, but require the use of suspensions of drug rather than solutions.
For injection directly into tumor tissue or tissue other than the bloodstream, higher concentrations of drug are of significant benefit and desirability, to provide higher drug loads and improved drug efficacy at or near the site of injection. Because the administration is not into the bloodstream, the presence of particulates is not proscribed. Reconstitution of cisplatin powder to a suspension rather than a solution, then, becomes of great interest.
U.S. Pat. No. Re 33,375, provides an example where a vial of lyophilized CDDP is first reconstituted with water for injection into a concentrated suspension of drug. A small amount of epinephrine solution is optionally added to this cisplatin suspension, then a portion of the suspension is withdrawn from the vial (via syringe and needle) and mixed with a collagen gel to yield a final gel preparation (containing a suspension of cisplatin) ready for administration.
Another example is provided in Theon et al. (1993) J. Am. Vet. Med. Assoc. 202:261-267, in which lyophilized CDDP is reconstituted with water to form a concentrated suspension of drug, then mixed with sesame oil to produce a water-in-oil emulsion that is subsequently injected directly into tumors in horses.
Reconstitution of lyophilized CDDP to a suspension in this fashion with water alone results in relatively large particles of drug which settle rapidly, resulting in inhomogeneous suspensions. This is turn results in CDDP preparations having CDDP content below the theoretical target value, and exhibiting considerable variability between nominally identical syringes of final gel. Methods which reduce the variability and improve recovery during suspension reconstitution are therefore of interest.
Relevant Literature
The use of collagen-based gels for delivery of chemotherapeutic drugs is described in U.S. Pat. No. Re. 33,375.
A non-aqueous suspension of CDDP in lipiodol.RTM. for transarterial chemoembolism is described in Araki et al. (1989) Gastrointest. Radiol. 14:46-48. Landrito et al. (1994) Cancer Chem. and Pharm. 34:323-330 teaches the effects of intralesional injection of cisplatin dissolved in urografin and lipiodol.RTM.. The treatment of hepatocellular carcinoma with a CDDP-epirubicin-lipiodol.RTM. suspension is described in Ichida et al. (1992) Cancer Chem. Pharm. 31:S51-S54.
The effects of intralesional vs. ip administration of cisplatin is described in Nagase et al. (1987) Cancer Treatment Reports 71:825-829. Theon et al. (1993) JAVMA 202:261-267 describes intratumoral chemotherapy with an oily emulsion of cisplatin.
Sternlicht et al. (1989) Radiology 170:1073-1075 investigates renal cisplatin chemoembolization with angiostat, gelfoam, and ethiodol. A combination chemoembolization therapy for hepatocellular carinoma is described in Yodono et al. (1989) Cancer Chem. and Pharm. 23:S42-S44. The reduction of systemic exposure and toxicity of cisplatin by encapsulation in poly-lactide-co-glycolide is taught by Verrijk et al. (1992) Cancer Res. 52:6653-6656.